Zühlke et al.

BMC Cardiovascular Disorders (2016) 16:46

DOI 10.1186/s12872-016-0225-3

RESEARCH ARTICLE Open Access

The natural history of latent rheumatic

heart disease in a 5 year follow-up study: a
prospective observational study
Liesl Zühlke1,2, Mark E. Engel1, Carolina E. Lemmer1, Marnie van de Wall1, Simpiwe Nkepu1, Alet Meiring2,3,
Michael Bestawros1,4 and Bongani M. Mayosi1*

Abstract
Background: Latent rheumatic heart disease (RHD) occurs in asymptomatic individuals with echocardiographic
evidence of RHD and no history of acute rheumatic fever. The natural history of latent RHD is unclear but has
important clinical and economic implications about whether these children should receive penicillin prophylaxis
or not. We performed a 5-year prospective study of this question.
Methods: In August 2013 through September 2014, we conducted a follow-up study of latent RHD among school
pupils using the World Heart Federation (WHF) echocardiographic criteria. Contingency tables were used to assess
progression, persistence or regression of latent RHD.
Results: Forty two borderline and 13 definite cases of RHD (n 55) were identified, 44 (80 %; mean age 13.8 ± 4.0 years;
29 (65.9 %) female) of whom were available for echocardiographic examination at a median follow-up of 60.8 months
(interquartile range 51.3-63.5). Over the follow-up period, half the participants (n = 23; 52.3 %) improved to normal or
better WHF category (regressors), a third (n = 14, 31.8 %) remained in the same category (persistors), while seven others
(15.9 %) progressed from borderline to definite RHD (progressors). In total, 21 subjects (47.7 %) reverted to a normal
status, nine (20.4 %) either improved from definite to borderline or remained in the borderline category, and 14
(31.8 %) either remained definite or progressed from borderline to a definite status. Two cases (20 %) progressed
to symptomatic disease.
Conclusions: Latent RHD has a variable natural history that ranges from regression to normal in nearly half of
cases, to persistence, progression or development of symptoms in the remainder of subjects.
Keywords: Latent rheumatic heart disease, Natural history, Outcome

Background refers to individuals with echocardiographic evidence of

There is a heavy burden of rheumatic heart disease (RHD)
in many developing countries and in some indigenous
communities of developed countries [1, 2]. RHD exacts
the highest number of disability-adjusted life-years of all
cardiovascular diseases among 10–14-year-olds (516 · 6
per 100 000 people, 95 % CI 425 · 3–647 · 0) and the sec-
ond highest number among children aged 5–9 years
(362 · 0 per 100 000 people, 294 · 6–462 · 0) [3]. There is
increasing recognition of the entity of latent RHD, which
* Correspondence: bongani.mayosi@uct.ac.za
1
The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and
University of Cape Town, Cape Town, South Africa
Full list of author information is available at the end of the article
RHD who have no history of acute rheumatic fever (ARF)
and no symptoms. [4, 5] It is possible that the early insti-
tution of penicillin in individuals with latent RHD may
prevent progression to overt clinical disease, but this has
not been established in prospective studies [6, 7].
There are several limitations with the existing studies
of the natural history of latent RHD detected by screen-
ing echocardiography [8–11]. First, three of the four
studies of this question to date used non-standardised
criteria for the diagnosis of RHD [8–10]. These criteria
are associated with widely varying estimates of the
prevalence of the disease even in the same population
[12]. The World Heart Federation (WHF) has developed

© 2016 Zühlke et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Zühlke et al. BMC Cardiovascular Disorders (2016) 16:46
new criteria for the echocardiographic diagnosis of latent
RHD that serve as the new consensus-based standard
for research in this field and allows for comparison of
data across communities and countries [13, 14]. These
criteria make a distinction based on age, with no border-
line category in those older than 20 years. Second, many
of these studies have reported variable use of penicillin
prophylaxis in patients with latent RHD, which may
change the natural history of the condition. Third, not
all patients with latent RHD were reported at follow-up,
with some studies only reporting changes in participants
with probable and possible disease [8]. Fourth, although
two studies reported the follow-up of latent RHD by
WHF criteria, they had relatively short follow-up periods
of 27–30 months [11, 15]. Finally, there is no informa-
tion on the outcome of latent RHD in subjects who are
older than 18 years [16–18].
We have used the WHF criteria to assess the natural
history of latent RHD disease diagnosed in childhood
over a period of five years into late adolescence and early
adulthood.
Methods
Study design
This is a prospective study of the natural history of la-
tent RHD diagnosed by echocardiography during the
course of a surveillance study in school pupils living in
the residential areas of Bonteheuwel and Langa of Cape
Town. The study protocol conforms to the ethical guide-
lines of the 1975 Declaration of Helsinki as reflected in a
priori approval by the human research committee of the
University of Cape Town. All participants gave written
parental consent and individual assent prior to the en-
rolment echocardiogram.
The sampling frame, selection of participants, and
echocardiographic protocol of the echocardiographic
surveillance study in Cape Town have been described in
full elsewhere [19]. The period of follow-up began in
January 2008 with the enrolment of the first participant
to September 2014 when the last participant was
followed-up. The scoring of the enrolment and follow-
up echocardiograms according to the WHF criteria oc-
curred in August 2013 through September 2014.
We invited all those diagnosed with latent RHD accord-
ing to the WHF criteria for a follow-up echocardiogram
by one examiner (LZ). A second reader (AM, CEL, MB,
or MvdW) reviewed the enrolment and follow-up echo-
cardiograms before final classification into definite RHD,
borderline RHD or normal study. The overall agreement
for definite disease was good (kappa 0.77, 95 % confidence
interval (CI) 0.71-0.83) and for borderline disease fair
(kappa 0.69; 95 % CI 0.65 to 0.73). All readers used the
same set of training echocardiograms to ensure consistent
application of the WHF criteria.
Page 2 of 6
Variables and Measurement
The WHF criteria have two abnormal categories for those
under the age of 20 years (i.e., borderline and definite
disease) and one abnormal category for those over the
age of 20 years (i.e., definite disease). We classified all
our participants at follow-up according to those guide-
lines, with the age-specific cut-offs for morphological
features [13]. Subsequent to this, we classified participants
into the following categories based on the review of the
enrolment and follow-up echocardiograms: persistors (i.e.,
diagnostic category unchanged), progressors (i.e., wors-
ened, e.g., from borderline to definite) or regressors (i.e.,
improved from definite to borderline or from borderline/
definite to normal).
Statistical considerations
We used mean, median, standard deviation and interquar-
tile range, where appropriate to describe the variables. We
explored univariate relationships using cross-tabulations
and calculated frequencies. We used contingency table
analyses to test differences between proportions using
Pearson-s Chi-squared test or Fisher’s exact tests as appro-
priate. This was followed by logistic regression analysis to
identify risk factors for persistence or progression of RHD.
We defined statistical significance as a two-sided P < 0.05.
Epi-Info software was used to manage the data, and the
statistical analysis was performed with Stata Version 11.2
(Cary, NC, USA).
Results
Participants
We invited 42 scholars with borderline and 13 with defin-
ite RHD at screening echocardiography for the follow-up
examination about 5 years later (n 55, median age
13 years). Forty-four participants (80 %) with a median age
of 18 years attended the follow-up echocardiogram. We
could not contact eleven participants for the following rea-
sons: nine (16 %) had left school with no contact details,
one (2 %) was overseas and another (2 %) refused to re-
turn for follow-up. Table 1 shows the age, gender and
follow-up duration of the 44 participants who underwent
repeat echocardiography, two of whom (4.6 %) were on
secondary antibiotic prophylaxis.
Natural history
Half the participants (n = 23; 52.3 %) improved over the
follow-up period to either borderline RHD or to a nor-
mal status. A third of the participants (n = 14, 31.8 %)
remained in the same WHF category while seven others
(15.9 %) worsened, progressing from borderline to defin-
ite RHD. The number of definite cases of RHD increased
from 10 cases at baseline to 14 cases at follow-up (40 %
Zühlke et al. BMC Cardiovascular Disorders (2016) 16:46
Table 1 Characteristics of the 44 schoolchildren with definite and probable rheumatic heart disease by the World Heart Federation
criteria at follow-up
Characteristic
Median age in years (IQR) (minimum, maximum) at initial diagnosis
Female sex – n (%)
Duration of follow-up, median months (IQR)
Median age in years (IQR) (minimum, maximum) at follow-up
Changes in diagnosis of RHD by age at review visit
Regressors (improved) n (%)
Persistors (remained the same) n (%)
Progressors (lesions worsened) n (%)
Ratio of persistors and progressors to regressors
IQR interquartile range
increase). The number of borderline cases of RHD fell
from 34 to nine while 21 became normal (47.7 %) (Fig. 1).
There were three types of outcomes of borderline RHD
(n 34, 77.3 %): (a) regression to normal (n 20, 58.8 %), (b)
persistent borderline state (n 7, 20.6 %), and (c) progression
to definite RHD (n 7, 20.6 %) (Fig. 1). The 9 borderline
cases that were identified at the follow-up visit had two
patterns of valve involvement: either pathological mi-
tral regurgitation (MR) (6 cases, 66.7 %) or at least two
morphological abnormalities of the mitral valve (3 cases,
33.3 %). There were no cases of pathological aortic regur-
gitation (AR) or cases with two or more morphological
features of the aortic valve.
Cases of definite RHD (n 10, 22.7 %) either remained
unchanged (n 7, 70 %) or improved to a borderline sta-
tus (n 2, 20 %) or reverted to normal (n 1, 10 %) (Fig. 1).
The 14 cases of definite RHD that were identified at the
follow-up visit displayed one of three patterns of valve
disease: 12 cases (85.7 %) had pathological MR with at
least two abnormal morphological features of the mitral
valve; one case (7.1 %) had pathological AR with at least
Fig. 1 Natural history of latent rheumatic heart disease in school
pupils after 60 months of follow-up
Page 3 of 6
Parameter (N =44)
13 (11–17) (5, 21)
29 (65.9)
60.2 (51.5-63.5)
18 (17–22) (10, 26)
Under 20 years Over 20 years Total
12 (42.9) 11 (68.8) 23 (52.3)
12 (42.9) 2 (12.5) 14 (31.8)
4 (14.2) 3 (18.7) 7 (15.9)
1.5 0.4 0.9
two abnormal features of the aortic valve; and one case
(7.1 %) had borderline disease of both aortic and mitral
valves. There were no cases of mitral stenosis.
There were 16 participants who were older than 20 years
at follow-up (range 21–27 years); the WHF criteria classify
borderline changes as normal in this age category. As a re-
sult, only five (31.3 %) still had evidence of latent RHD,
while 11 (68.7 %) had reverted to normal. Of the five with
latent RHD, two had persistent disease (12.5 %), whilst
three had progressed from borderline to definite RHD
(18.7 %).
Factors to determine persistence or progression
There was no significant association of age at diagnosis
(P = 0.582), gender (P = 0.61) or residential area (P = 0.08)
with persistent or progressive RHD. On echocardiographic
features, only pathological MR was associated with persist-
ent RHD (P = 0.03). Pathological MR had an area under
the receiver-operating characteristic curve of 0.69, 95 % CI
0.54 to 0.83 for predicting the persistence of either definite
RHD or borderline RHD (Table 2).
Symptomatic disease
There were two cases that developed clinical symptoms
of RHD over the five year period. The first patient was a
16-year-old girl first seen four years and three months
earlier with definite RHD (i.e., pathological MR and two
additional morphological features of the mitral valve on
echocardiogram). Upon follow-up, she presented with
symptoms and signs of cardiac failure at eight weeks of
pregnancy, and echocardiography revealed pathological
MR and three abnormal morphological features of the
mitral valve with normal left ventricular function. We
commenced her on diuretics and referred her to a tertiary
centre. She had been adherent to monthly benzathine
penicillin and had no history of either sore throat or
episodes of ARF.
Zühlke et al. BMC Cardiovascular Disorders (2016) 16:46
Table 2 Echocardiographic features associated with progression or persistence of rheumatic valvular lesions
Normal on follow-up
N = 21 (47.7.)
Demographic features
Female gender 13 (44.8)
Langa suburb 17 (56.7)
Echocardiographic features on screening
Pathological mitral regurgitation n (%) 9 (33.3)
Pathological mitral valve morphology n (%) 11 (55)
Anterior mitral valve thickness > = 3 mm 13 (44.8)
Chordal thickness 3 (33.3)
Restricted leaflet motion 10 (66.7)
Excessive leaflet motion 3 (60)
Pathological aortic regurgitation n (%) 2 (28.6)
The second patient was 22 years old, enrolled 5 years
and 3 months prior to the follow-up visit with borderline
RHD (pathological MR). She had tested positive for hu-
man immunodeficiency virus (HIV) prior to the follow-up
visit but was non-adherent to anti-retroviral therapy.
Upon follow-up, she had severe MR, an increased left ven-
tricular end-diastolic diameter of 57 mm (Z score 2.55)
and decreased left ventricular ejection fraction of 45 %.
She had no history of sore throat or symptoms consistent
with ARF and was subsequently lost to follow-up.
Discussion
There are at least three key findings of this study. First,
echocardiographic changes that were suggestive of latent
RHD diagnosed by the WHF criteria in school pupils re-
vert to normal in almost half the cases when followed
for five years. This was more evident in those over the
age of 20 years at follow-up, three quarters of whom
reverted to normal. Second, definite or borderline RHD
in asymptomatic scholars with no history of ARF is a dy-
namic phenotype, which may regress to normal, remain
unchanged, or progress to more severe and even symp-
tomatic disease in a small proportion affected individ-
uals. Finally, the natural history of borderline RHD was
associated with greater improvement than definite RHD,
probably because of a lack of a borderline category in
participants over the age of 20 years in the WHF criteria.
More than half of the cases in the borderline category
reverted to normal (n = 20, 58.8 %) compared to only
one case (10 %) in the definite category. However, the
two cases that progressed to symptomatic disease were
in each diagnostic category, indicating that the border-
line RHD category identifies cases that are at risk of clin-
ical RHD.
This study extends the existing knowledge on the out-
come of latent RHD in several ways. First, we show that
the strict use of WHF criteria in subjects older than
Page 4 of 6
RHD on follow-up p
N = 23 (52.3)
16 (55.2) 0.61
13 (43.3) 0.08
18 (66.7) 0.03
9 (45) 0.37
16 (55.2) 0.75
6 (66.7) 0.46
5 (33.3) 0.11
2 (40) 0.65
5 (71.4) 0.42
20 years is associated with a greater proportion of cases
that are classified as normal because of the lack of the
category in this group. The clinical significance of the re-
classification of participants with borderline changes to
normal by virtue of age warrants further study. Second,
we show that a longer duration of follow-up may be asso-
ciated with a larger proportion of cases with improvement
in rheumatic valvular lesions. Whereas previous studies
with a follow-up ranging from 6 months to 30 months
have shown improvement in 28 % to 39 % of cases [8–11],
52 % of cases improved in this study (Fig. 2). Finally, only
2/44 cases (4.6 %) were receiving secondary antibiotic
prophylaxis during the follow-up period. This is therefore
a true natural history study of latent RHD over a long
period of time. It is of interest that one of the two patients
on antibiotic prophylaxis in fact progressed to overt
clinical RHD.
Previous natural history studies of latent RHD have
reported the persistence or progression of lesions in
53-68 % of cases over 6 months to 30 months of
follow-up; our study falls in the lower border of this
estimate with about 48 % of persistence or progression
(Fig. 2) [8–11]. Other studies have also found the pre-
dictive value of definite RHD and significant mitral
valve disease for persistent or progressive disease. In
contrast, other investigators have shown that morpho-
logic abnormalities are associated with persistence and
progression of disease, which was not the case in this
study [11]. It is possible that the determination of
morphological abnormality on the heart valves is subject
to greater observer variation, confounded by technical set-
tings of echocardiography, and affected by the prevalence
of other conditions such as endomyocardial fibrosis in the
background population.
Our study has several limitations. First, the sample size
is small; it is therefore more likely to generate a hypoth-
esis rather than provide a definite answer to the question
Zühlke et al. BMC Cardiovascular Disorders (2016) 16:46
Fig. 2 A comparison of the natural history of latent rheumatic heart disease in five studies with increasing durations of follow-up.
Acronyms m = months of follow-up, n = sample size of follow-up cohort
of the natural history of echocardiographic RHD in
asymptomatic school pupils. A prospective, international,
multi-centre registry of definite and borderline RHD
(known as the “DefineRHD” registry) is underway to
address the concerns regarding the natural history in a
large number of cases [5]. Second, we did not perform
auscultation at the time of enrolment of the participants
in this study. This decision was made on the basis of the
superior performance of echocardiography in the detec-
tion of latent RHD [20]. Therefore this is a study of
asymptomatic RHD, which cannot address the question of
the outcome of subclinical (i.e., without murmur) versus
clinical (i.e., with murmur) forms of latent RHD. Third,
this study cannot make inferences regarding the time
interval from the initial attack of ARF to entry into this
five year observation period. It is possible that individuals
in their third decade actually had an attack of ARF more
than 10 years previously while younger individuals had the
attack of ARF only one or two or even three years prior to
being enrolled in the study. A recent paper [15] suggests
that screened children in an endemic area should be
followed as both groups (latent RHD and initially normal)
can develop episodes of ARF in the following years. Fi-
nally, the 20 % loss to follow-up rate is a matter of con-
cern, but is comparable to other studies in this field due to
migration of participants after leaving school [8–11].
We undertook several measures to minimise bias in this
study. Firstly, the random ascertainment of the participants
in the surveillance sought to ensure the generalizability
of finding to school going population of the Bonteheuwel
and Langa communities of Cape Town. Secondly, we in-
vited all available participants with abnormal enrolment
Page 5 of 6
echocardiograms to participate in the follow-up study. We
based our study size therefore on the number of partici-
pants with abnormal echocardiograms identified at the time
of original ascertainment. Finally, one observer applied the
WHF criteria to the baseline and follow-up echocardio-
grams, with verification of findings by a second observer.
Despite the limitations, our findings do have important
implications for clinical practice and research. It is clear
from this and other studies that a diagnosis of latent RHD
on echocardiography requires confirmation in follow-up
studies due to the dynamic nature of the condition – which
may resolve, persist or deteriorate [8–11]. According to
existing studies, a minimum follow-up period of 12 months
may be reasonable to identify cases who regress to normal,
although our study suggests that a longer duration of up to
five years (into late adolescence and early adulthood) may
identify a higher proportion of cases that regress to normal.
The management of those with persistent subclinical RHD
is unknown [21]. Whilst some authorities have recom-
mended the institution of secondary antibiotic prophylaxis
to prevent progression to overt RHD, this advice is not
based on randomised controlled evidence [21, 22]. There-
fore, there is need for adequately powered randomised
controlled trials of antibiotic prophylaxis to determine
the effectiveness and safety of secondary antibiotic
prophylaxis in preventing morbidity and mortality asso-
ciated with persistent latent RHD [6, 21].
Conclusions
Latent RHD resolves to normal in nearly half of school
pupils followed up for 5 years. There is therefore a need
to repeat echocardiography in these cases before an
Zühlke et al. BMC Cardiovascular Disorders (2016) 16:46
intervention is considered. The effectiveness and safety
of secondary antibiotic prophylaxis in persistent latent
RHD needs to be tested in large randomised controlled
trials.
Abbreviations
AR: Aortic regurgitation; ARF: Acute rheumatic fever; HIV: Human
immunodeficiency virus; MR: Mitral regurgitation; RHD: Rheumatic heart
disease; WHF: World Heart Federation.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
The idea for this study was conceived by BMM, and LZ wrote the first draft
of the manuscript. LZ, MEE, and BMM designed the study, and the analysis
and interpretation of data. LZ, CEL, MvdW, SN, AM, and MB made substantial
contributions to the acquisition of data. All authors have been involved in
revising the manuscript critically for important intellectual content, have
given final approval of the version to be published, and agree to be accountable
for all aspects of the work in ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately investigated and resolved.
Acknowledgements
The authors would like to thank Ms Peggy Mgwayi for administrative
assistance in contacting subjects.
We acknowledge the following organisations for grant support: Life
Healthcare Foundation, South African Medical Research Council, Lily and
Ernst Hausmann Research Trust, Else Kröner Fresenius Foundation, University
of Cape Town, National Research Foundation of South Africa, World Heart
Federation, US National Institutes of Health Fogarty International Clinical
Research Fellowship (LZ), Thrasher Research Fund Early Career Award (LZ),
Wellcome Trust Clinical Infectious Disease Research Initiative (CIDRI) Research
Officer Award (LZ), and the Hamilton Naki Clinical Scholarship (LZ).
Author details
1
The Cardiac Clinic, Department of Medicine, Groote Schuur Hospital and
University of Cape Town, Cape Town, South Africa. 2Division of Paediatric
Cardiology, Department of Paediatrics and Child Health, Red Cross War
Memorial Children’s Hospital and University of Cape Town, Cape Town,
South Africa. 3Present address: Division of Cardiology, Department of Internal
Medicine, Tygerberg Hospital and Stellenbosch University, Parow, South
Africa. 4Present address: New Mexico Heart Institute and the University of
New Mexico, Albuquerque, NM, USA.
Received: 7 November 2015 Accepted: 12 February 2016
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